The long-term objectives of this competing renewal are to develop novel therapeutics for periodontitis by inhibiting nuclear factor-kappa B (NF-kB). Periodontitis is the most common inflammatory disease and often destroys periodontal tissues and alveolar bone, resulting in loss of tooth support. More importantly, growing evidence suggests that chronic periodontal inflammation is an important risk factor for cardiovascular disease, oral cancer, diabetes and other systemic diseases. Thus, it represents a significant public concern in the aging population. Multiple pro-inflammatory molecules, including tumor necrosis factor (TNF), interleulin-1 (IL-1), IL-6, IL-8, intercellular adhesion molecule-1, cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP)-1, and MMP-9, are associated with periodontal inflammation and bone loss. Basic science discoveries from our group and others have demonstrated that NF-kB is a master transcription factor that controls the expression of pro-inflammatory molecules. Using genomic and bioinformatic approaches, we have found that the majority of early-response genes induced by periodontal pathogens are dependent on NF-kB. Recently, we also discovered that the activation of NF-kB mediates the uncoupling of bone formation from bone resorption, providing a novel explanation for the compromised repair in periodontitis. Therefore, from the standpoint of developing novel therapeutics for periodontitis, targeting NF-kB may be more effective than single cytokines. In screening for novel molecules that inhibits NF-kB, unexpectedly, we discovered that Wnt-4 proteins inhibited periodontal inflammation and promoted repair in vitro and in vivo. Based on our preliminary studies, in this competing renewal, we hypothesize that Wnt-4 prevents periodontal inflammation and bone loss by attenuating NF-kB activation. Three specific aims are proposed to test our hypothesis. Aim 1 is to determine whether Wnt-4 prevents periodontal inflammation and alveolar bone loss by attenuating NF-kB activation in vivo. Aim 2 is to explore whether recombinant Wnt-4 proteins can inhibit the progression of periodontitis and maintains alveolar bone formation by attenuating NF-kB activation in vivo. Aim 3 is to explore the molecular mechanisms by which Wnt-4 suppresses NF-kB activation induced by inflammatory mediators. The results should provide an important proof-of-principal in the prevention and treatment of periodontitis by targeting NF-kB, and lay the important foundation for the clinical trials involving the IKK/NF-kB inhibitors. PUBLIC HEALTH RELEVANCE: Periodontitis is the most common inflammatory disease and often destroys alveolar bone and periodontal tissues, resulting in loss of tooth support. It is estimated that over 80% of adults over age 30 have periodontal bone loss and 50% of adults over age 60 have advanced periodontitis with several loose teeth due to severe bone loss. More importantly, growing evidence suggests that chronic periodontal inflammation is an important risk factor for cardiovascular disease, oral cancer, diabetes and other systemic diseases. Thus, it represents a significant public concern in the aging population. In this application, we will tet Wnt-4 proteins can inhibit gum diseases and prevent tissue destruction by attenuating inflammatory responses in vitro and in vivo. The findings from this study will have important implications in developing novel biological strategies for treating gum diseases or other inflammatory diseases.